Type 2 diabetes mellitus (T2DM), which is highly prevalent among Veterans, increases the risk of cognitive impairment and dementia, including Alzheimer?s disease (AD). We have shown that T2DM?even during midlife?is associated with steeper cognitive decline, reduced cerebral blood flow (CBF) in regions that are predilection sites for AD pathology, and greater neuropathologic changes at autopsy (Bangen et al., 2013; Bangen et al., 2016; Bangen et al., in prep). Identifying individuals who are most likely to decline prior to the occurrence of significant brain changes is essential, so that interventions can be applied before extensive cerebrovascular lesions and cognitive changes develop. Accordingly, studies investigating incipient cognitive and neuroimaging changes in middle age when neuropathologic changes are already occurring are critical to optimize brain health and improve outcomes in T2DM and other high-risk populations. Most previous neuroimaging studies of brain changes underlying cognitive impairment in T2DM have applied conventional structural magnetic resonance imaging (MRI) to detect end-stage macrostructural changes associated with cerebrovascular disease (CVD) such as white matter hyperintensities (WMH) and infarcts. However, recent advances in MRI have allowed for the development of sensitive, sophisticated methods for the non-invasive measurement of cerebral blood flow (CBF) and cerebral arterial compliance (AC), or the ability of vessels to distend or increase in volume in response to changes in blood pressure. Such methods may help elucidate the mechanisms that precede the development of irreversible parenchymal/structural damage and may also yield important markers of risk for cognitive decline in at-risk populations. Although T2DM has been associated with peripheral arterial stiffening using carotid-femoral pulse wave velocity, no studies have examined intracranial arterial stiffening (i.e., decreased AC) in the context of T2DM. We therefore propose to advance the field by assessing neuropsychological functioning, macrovascular AC and microvascular CBF, and established MR markers of AD and cerebrovascular disease in a sample of 120 middle-aged Veterans with and without a diagnosis of T2DM (aged 45-60). Participants will undergo comprehensive neuropsychological assessment; laboratory testing to assess blood-based markers related to glycemia, inflammation, and endothelial function; CSF measurement of amyloid and tau; and neuroimaging exams including high resolution structural imaging and highly novel arterial spin labeling (ASL) MRI methods that estimate cerebral arterial compliance and blood flow. The goals of this project are to investigate whether early changes in cerebrovascular functioning (i.e., reduced AC and CBF) relate to MRI markers of CVD lesions, AD markers, and cognition in T2DM. We will also investigate whether potentially modifiable factors such as inflammation and endothelial dysfunction alter associations between AC, CBF, CVD markers, AD markers, and cognition. Findings will help address an important and pressing public health need by identifying biomarkers of cognitive decline in T2DM and elucidating potentially modifiable mechanisms underlying these changes. Results are also expected to assist in facilitating targeted interventions in order to reduce dementia risk while improving the health and functioning of Veterans with T2DM.